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Background: Glutaminase 1 (GLS1), a key enzyme in glutamine metabolism in cancer cells, acts as a tumor promoter and could be a potential therapeutic target. CB-839, a GLS1-specific inhibitor, was developed recently. Herein, we aimed to elucidate the anti-tumor effects and mechanism of action of CB-839 in colorectal cancer (CRC)., Methods: Using the UCSC Xena public database, we evaluated GLS1 expression in various cancers. Immunostaining for GLS1 was performed on 154 surgically resected human CRC specimens. Subsequently, we examined the GLS1 mRNA expression levels in eight CRC cell lines and evaluated the association between GLS1 expression and CB-839 efficacy. To create a reproducible CRC model with abundant stroma and an allogeneic immune response, we co-transplanted CT26 and stem cells into BALB/c mice and treated them with CB-839. Finally, RNA sequencing of mouse tumors was performed., Results: Database analysis showed higher GLS1 expression in CRC tissues than in normal colon tissues. Clinical samples from 114 of the 154 patients with CRC showed positive GLS1 expression. GLS1 expression in clinical CRC tissues correlated with vascular invasion. CB-839 treatment inhibited cancer cell proliferation depending on GLS1 expression in vitro and inhibited tumor growth and metastasis in the CRC mouse model. RNA sequencing revealed that CB-839 treatment inhibited stromal activation, tumor growth, migration, and angiogenesis. These findings were validated through in vitro and in vivo experiments and clinical specimen analysis., Conclusions: GLS1 expression in CRC plays important roles in tumor progression. CB-839 has inhibitory effects on cancer proliferation and the tumor microenvironment., Competing Interests: Declaration of competing interest No conflicts of interest exist for any of the authors., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Non-Helicobacter pylori Helicobacter (NHPH) has recently been linked to various gastric diseases. However, the relationship between NHPH infection and gastric cancer remains controversial. This study aimed to identify the effect of NHPH infection on gastritis and gastric cancer development., Materials and Methods: Formalin-fixed paraffin-embedded tissues were obtained from 73 patients with gastric cancer, of whom 21 cases were Helicobacter pylori (Hp) current infection, 37 cases were Hp previous infection, and 15 cases were Hp naïve infection, and were screened for NPHPs using polymerase chain reaction. The results were compared with NHPH infection rates in the patients with gastritis-related diseases reported in the previous study. We evaluated the association of NHPH infection with gastritis and clinicopathological features of gastric cancer., Results: NHPH infection rates were 4/21 (19%) in "Hp current" patients, 4/37 (11%) in "Hp previous" infection patients, and 1/15 (7%) in "Hp naïve" patients, showing no significant difference in infection rates based on Hp infection status. NHPH infection rates in gastric cancer patients were similar to those in the patients with gastritis-related diseases reported in the previous study. A comparison of NHPH-positive and negative patients showed no significant differences in atrophic gastritis status, serum gastritis markers, or clinicopathological characteristics of gastric cancer, such as localization, size, gross type, differentiation, or depth., Conclusions: The association between gastric cancer and NHPH infection would have important implications for gastric cancer prevention, diagnostics, and treatment, however, no significant association was found in this particular population., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to be declared for any of the authors., (Copyright © 2023 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Objectives: Patients with histological variants (HV) of bladder cancer have more advanced disease and poorer survival rates than those with pure urothelial carcinoma (UC). Moreover, lymphovascular invasion (LVI) is an important biomarker after RNU in systematic reviews and meta-analyses. Thus, here we investigated the clinical and prognostic impact of HV and LVI in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU)., Methods: Data from 223 UTUC patients treated with RNU without neoadjuvant chemotherapy were retrospectively evaluated. We analyzed differences in clinicopathological features and survival rates between patients with pure UC and those with HV. Conditional survival (CS) analysis was performed to obtain prognostic information over time., Results: A total of 32 patients (14.3%) had HV, with the most common variant being squamous differentiation, followed by glandular differentiation. UTUC with HV was significantly associated with advanced pathological T stage (pT ≥ 3), higher tumor grade (G3), and LVI, compared to pure UC (all P < 0.01). Progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS), were all significantly worse in the HV group compared to the pure UC group (all, P < 0.001). In multivariable analysis, HV and LVI were independent predictors of CSS and OS. We classified the patients into three groups using these two predictors: low-risk (neither HV nor LVI), intermediate-risk (either HV or LVI), and high-risk (both HV and LVI). Significant differences in PFS, CSS, and OS rates were found among the 3 groups. In CS analysis, the conditional PFS, CSS, and OS rates at 1, 2, 3, 4, and 5 years improved with increased duration of event-free survival. CS analysis revealed that most progression events occurred within 2 years after RNU, and patients with risk factors had worse PFS at all time points., Conclusions: A risk model using HV and LVI can stratify PFS, CSS, and OS of patients treated with RNU. In addition, CS analysis revealed that HV and LVI were poor prognostic factors over time after RNU., Competing Interests: Conflict of interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Histologic tumor necrosis (TN) is a well-established independent prognostic indicator in patients treated surgically for clear cell renal cell carcinoma (ccRCC). However, the precise mechanisms by which TN alters disease progression remain unknown. The DEAD-box protein DDX41, a member of a large family of helicases, has been characterized as a pattern recognition receptor against an array of double-stranded (ds)DNA produced from bacteria, dsDNA viruses, and nearby cells that have released dsDNA fragments through necrosis. We hypothesized that DDX41 expression may be upregulated in ccRCC with TN, leading to worse prognosis., Methods: Relationship between the presence of TN and DDX41 expression were examined using The Cancer Genome Atlas data sets or using ccRCC samples in our institution. Further, the molecular functions of DDX41 were investigated with human ccRCC cells., Results: The presence of TN was significantly associated with the upregulation of mRNA and protein expression of DDX41 in the 2different patient cohorts with ccRCC. In addition, the mRNA and protein expression levels of DDX41 revealed a worse prognosis. In vitro analyses with ccRCC cells revealed that DDX41 expression promotes tumor-promoting activity. Furthermore, VHL loss, 1of the most common features in ccRCC, was shown to play an extremely important role in increasing the expression of the CXCL family in DDX41-expressing ccRCC, leading to the acquisition of a worse malignant phenotype., Conclusions: DDX41 expression is associated with TN in ccRCC and leads to a worse prognosis in cooperation with VHL loss., Competing Interests: Conflict of interest All authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Background: Anti-inflammatory therapy targeting interleukin (IL)-1β reduced cardiovascular events in a randomized trial. We evaluated the relationship between IL-1β mRNA expression in epicardial adipose tissue (EAT) and clinically-assessed coronary atherosclerosis on computed tomography (CT)., Methods: We studied 45 patients before cardiac surgery (coronary artery bypass grafting [CABG], n ​= ​18; non-CABG, n ​= ​27). EAT volume, the coronary calcium score (CCS), and the presence of non- and/or partially-calcified coronary plaques (NCPs) and high-risk coronary plaques (HRPs; minimum CT density <30 Hounsfield units and vascular remodeling index >1.1) on CT angiography were assessed. EAT samples were obtained during cardiac surgery. IL-1β mRNA expression in EAT was measured using quantitative real-time PCR and normalized to that of β-actin in each patient., Results: There was no difference in IL-1β mRNA levels between patients who were scheduled for CABG and non-CABG surgery or among subgroups based on the CCS. However, patients with NCPs (median [interquartile range], 4.1[2.0-11.6]E-4 versus 1.8[0.6-4.5]E-4, p ​= ​0.024) and HRP (7.6[3.0-20.4]E-4 versus 1.9[0.7-4.3]E-4, p ​= ​0.0023) had higher IL-1β mRNA levels than those without these plaques. On multivariate analysis adjusted for age, sex, coronary risk factors, statin therapy, CCS, and EAT volume, the presence of HRPs was significantly correlated with elevated IL-1β mRNA levels in EAT (β ​= ​0.39, p ​= ​0.047)., Conclusion: Our data suggest a contribution of EAT to coronary atherosclerosis through molecular behavior, such as IL-1β gene expression, which may be a new therapeutic target., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to disclose., (Copyright © 2020 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Introduction: Microtubule-associated protein tau (MAPT) overexpression has been linked to poor prognosis in several cancers. MAPT-AS1 is a long noncoding RNA existing at the antisense strand of the MAPT promoter region. The clinical significance of MAPT and MAPT-AS-1 in clear cell renal cell carcinoma (ccRCC) is unknown. This study aimed to assess the expression and function of MAPT and MAPT-AS1 in ccRCC., Methods: The expression of MAPT was determined using immunohistochemistry in ccRCC. The effects of MAPT knockdown on cell growth and invasion were evaluated and the interaction between MAPT and microtubule-associated protein tau antisense (MAPT-AS1) were analyzed. The expression of MAPT-AS1 was determined using quantitative reverse transcription polymerase chain reaction in ccRCC tissues. We investigated the effect of MAPT-AS1 knockdown on cell growth and invasion. We analyzed the regulation of MAPT and MAPT-AS1., Results: Immunohistochemistry in 135 ccRCC cases showed that 61% of the cases were positive for MAPT. Kaplan-Meier analysis showed that the low expression of MAPT was associated with poor overall survival after nephrectomy. Knockdown of MAPT enhanced cell growth and invasion. quantitative reverse transcription polymerase chain reaction revealed a positive correlation between MAPT and MAPT-AS1. The expression of MAPT-AS1 was higher in ccRCC tissue than in nonneoplastic kidney tissue. Kaplan-Meier analysis showed that the low expression of MAPT-AS1 was associated with poor overall survival after nephrectomy by in silico analysis. MAPT-AS1 knockdown promoted cell growth and invasion activity. P53 knockout suppressed the expression of MAPT and MAPT-AS1., Conclusion: These results suggest that MAPT and MAPT-AS1 may be promising predictive biomarkers for survival and play a tumor-suppressive role in ccRCC., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Prostate cancer (PCa) is a common malignancy worldwide. Docetaxel has been an important treatment option for patients with metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients with CRPC treated with docetaxel eventually become refractory. In the present study, we analyzed the expression and distribution of kinesin family member C1 (KIFC1) in human PCa by immunohistochemistry and examined the effect of inhibiting KIFC1 expression on docetaxel resistance., Methods: Expression of KIFC1 was determined using immunohistochemistry. RNA interference was used to inhibit KIFC1 expression in PCa cell lines. To examine cell viability, we performed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays., Conclusions: These results indicate that KIFC1 plays an important role in PCa progression. Immunohistochemical analysis of KIFC1 would facilitate identification of patients with poor prognoses after radical prostatectomy, as well as patients with poor therapeutic outcomes after docetaxel-based chemotherapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Previous studies indicate that epicardial adipose tissue (EAT) biologically contributes to the progression of coronary atherosclerosis. We evaluated the relationship between EAT pathology, represented by inflammation and neoangiogenesis, and coronary atherosclerosis on computed tomography (CT) images., Methods: We performed CT examination in 45 patients scheduled for cardiac surgery (coronary artery bypass graft [CABG], n = 21; non-CABG, n = 24) to assess visceral adipose tissue (VAT) area, EAT volume, coronary calcium score (CCS), and presence of non-calcified coronary plaque (NCP) on CT angiography. Each patient was assessed with the numbers of CD68(+) individual macrophages and CD31(+) neovessels in six random high-power fields (400×) of EAT samples subsequently obtained during cardiac surgery., Results: In three groups based on CCS (mild, 0-100; moderate, 101-400; severe, >400), the moderate group had the most extensive macrophage infiltration (p = 0.0025) and neoangiogenesis (p = 0.0036) in EAT. The patients with NCP had more extensive macrophage infiltration (p = 0.010) and neoangiogenesis (p = 0.0043) in EAT than those without. On multivariate analysis adjusted for age, sex, CABG versus. non-CABG, VAT area, and EAT volume, moderate CCS and the presence of NCP showed significant correlations with increased macrophage infiltration (β = 0.65; p < 0.0001, and β = 0.49; p = 0.0089, respectively) and neoangiogenesis (β = 0.55; p = 0.0011, and β = 0.53; p = 0.012, respectively) in EAT., Conclusion: Inflammation and neoangiogenesis in EAT independently correlate with moderate coronary calcification and presence of NCP, suggesting that these two factors may have a role in promoting coronary atherosclerosis., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Although chemotherapy for castration-resistant prostate cancer (CRPC) has been applied clinically in recent years, the effects are not sufficient. It is urgently necessary to develop novel therapeutics for CRPC. We previously generated Escherichia coli ampicillin secretion trap libraries of 2 prostate cancer (PCa) cell lines and normal prostate. By comparing the E. coli ampicillin secretion trap libraries of CRPC cell lines with those of androgen-sensitive PCa cell lines and normal prostate, we focused on the protein-tyrosine-phosphatase of regenerating liver 1 (PRL1) gene and analyzed its expression and biological function., Materials and Methods: The expression of PRL1 was examined by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in clinical PCa samples. The effects of PRL1 on PCa cells were evaluated by cell growth, migration, and invasion assays. To investigate the effect of PRL1 on epidermal growth factor receptor (EGFR) signaling, PRL1 knockdown PC3 cells were examined by Western blot and immunohistochemical analyses., Results: Quantitative reverse transcription polymerase chain reaction revealed that PRL1 was expressed much more highly in PCa than in nonneoplastic prostate samples. High expression of PRL1 detected by immunohistochemistry correlated with poor prognosis after prostatectomy and combined androgen blockade therapy. Functional analysis indicated that PRL1 stimulated cell growth, migration, and invasion in PCa cell lines. Expression EGFR and matrix metalloproteinase 9 was reduced by knockdown of PRL1 in the PC3 cell line., Conclusions: PRL1 regulates expression of EGFR and modulates downstream targets. PRL1 has potential as a therapeutic target in PCa including CRPC., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We generated transgenic mice in which human CDX2 gene elements control expression of a tamoxifen-regulated Cre protein (CDX2P-CreER(T2)) to allow for inducible gene targeting in intestinal epithelium. After tamoxifen dosing of CDX2P-CreER(T2) mice, Cre activity was detected in the distal ileal, cecal, colonic, and rectal epithelium, with selected crypt base, transit amplifying, and surface cells all capable of activating Cre function. Four weeks after tamoxifen dosing of CDX2P-CreER(T2) mice carrying a Cre-activated fluorescent reporter, single crypts were uniformly fluorescence positive or negative, reflecting Cre activation in crypt stem cells. Biallelic inactivation of the Apc tumor suppressor gene via the CDX2P-CreER(T2) transgene in colon epithelium led to acute alterations in cell proliferation, apoptosis, and morphology, along with mitotic spindle misorientation, β-catenin nuclear localization, and induction of the intestinal stem cell markers Lgr5 and Musashi-1 and the Sox9 transcription factor. Normal mouse colon epithelium lacks Paneth cells, a key small intestine niche cell type, and Paneth cell differentiation is dependent on Sox9 function. In Apc-deficient colon epithelium, ectopic Paneth-like cells were seen outside the crypt base, such as new crypt budding sites. Our data indicate Apc inactivation via CDX2P-CreER(T2) targeting in mouse colon epithelium is sufficient to induce adenomatous changes and the generation of Paneth-like cells from neoplastic progenitors, with potentially significant roles in colon adenoma development and progression., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)